Harnessing host enhancers of SARS-CoV-2 entry as novel targets for antiviral therapy
SUMMARY
The WHO declared the official end of the SARS-CoV-2 caused public health emergency on May 5th, 2023, after two years in which the virus infected approximately 750 Mio individuals, causing estimated up to 7 Mio deaths. Likely, the virus will continue to evolve in the human population as a seasonal respiratory pathogen. To now prevent severe infection outcomes in vulnerable individuals, effective antivirals are urgently needed to complement the protection provided by vaccines. SARS-CoV-2 enters its host cell via ACE2-mediated membrane fusion, either at the plasma membrane, if the protease TMPRSS2 is present or via the endosome, in a cathepsin-dependent fashion. A small number of positive regulators of viral uptake were described in the literature, which are potentially useful targets for host-directed antiviral therapy or biomarkers indicating increased or diminished susceptibility to infection. The authors of this article, led by GCIR Professor Mirco Schmolke, identified here by cell surface proximity ligation novel proteins, required for efficient virion uptake. Importantly, chemical inhibition of one of these factors, SLC3A2, resulted in a robust reduction of viral replication, to that achieved with a TMPRSS2 inhibitor. Their screen identified new host dependency factors for SARS-CoV-2 entry, which could be targeted by novel antiviral therapies.
Full article: https://doi.org/10.1016/j.antiviral.2024.105951
WHY IS IT IMPORTANT?
Recent research has identified new host proteins that facilitate the entry of SARS-CoV-2 into human cells, which could be targeted for antiviral therapy. The virus typically uses ACE2 to enter cells, with the crucial help of the enzyme TMPRSS2, but from the present study, we now know that this process also relies on proteins such as SLC3A2 and ADAM10. Using a technique called cell-surface proximity ligation, researchers in GCIR Professor Schmolke's group discovered that these proteins are critical for efficient virion uptake. Chemical inhibition of SLC3A2 significantly reduced viral replication, comparable to TMPRSS2 inhibitors. This suggests that SLC3A2 is a viable target for developing new antiviral therapies.
The study underscores the flexibility of SARS-CoV-2 entry mechanisms and highlights the potential of host-dependent factors to combat viral infections, complementing current vaccination strategies, which is of specific importance to patients with weak vaccine responses.
2 Jul 2024